Sirtuins are a class of evolutionally conserved enzymes with NAD-dependent protein deacetylase activity (FIG. 1) (Sauve et al., Annu. Rev. Biochem. 75: 435-465 (2006), Michan et al., Biochem. J. 404: 1-13 (2007)). Since the initial reports that sirtuins exhibit deacetylase activity, they have been implicated in a number of cellular and biological functions including the regulation of life span, transcription, and metabolism (Sauve et al., Annu. Rev. Biochem. 75: 435-465 (2006), Michan et al., Biochem. J. 404: 1-13 (2007)). There are seven sirtuins in mammals, Sirt1-7; however, only Sirt1-3 have been shown to be capable of robust deacetylase activity. Sirt4 and 7 lack detectable deacetylase activity (Michishita et al., Mol. Biol. Cell 16:4623-4635 (2005), Haigis et al., Cell 126: 941-954 (2006)), whereas Sirt5 and Sirt6 were reported to have only weak activity (Michishita et al., Mol. Biol. Cell 16:4623-4635 (2005), Schuetz et al., Structure 15: 377-389 (2007), Schlicker et al., J. Mol. Biol. 382: 790-801 (2008), Michishita et al., Nature 452: 492-496 (2008)). It has been recently discovered that human Sirt5 is an NAD-dependent desuccinylase and demalonylase (Du et al., Science 334: 806-809, 2011). It has also been found that many mitochondrial metabolic enzymes are succinylated and Sirt5 can regulate the activity of certain enzymes by desuccinylation.
Some sirtuins have been suggested to play a role in cancer development or tumor suppression (Verdin et al., Trends Biochem. Sci. 35: 669-675 (2010), Ota et al., Oncogene 25: 176-185 (2005), Heltweg et al., Cancer Res. 66: 4368-4377 (2006), Lara et al., Oncogene 28: 781-791 (2008), Zhang et al., Biochem. Biophys. Res. Commun. 386: 729-733 (2009), Kalle et al., Biochemical and Biophysical Research Communications 401: 13-19 (2010)). It is still not clear whether inhibiting sirtuins and which sirtuins could be used as a potential anti-cancer therapy (Verdin et al., Trends Biochem. Sci. 35: 669-675 (2010)).